Our novel, preliminary data have lead to the hypothesis that insulin is an important regulator of the cerebral circulation and that the magnitude of this effect is impaired with aging and the metabolic syndrome. This important research area is totally unexplored. Our data show for the first time that insulin, at levels which are equivalent to those reached in blood several times each day during meals, is able to have dramatic effects on cerebral vascular tone and cerebral blood flow (CBF). In addition, the effect of insulin at very high levels which are associated with replacement therapy in diabetic patients has never been investigated. Furthermore, many of the initial elements of the insulin signaling cascade in cerebral arteries are similar to those that we have found to promote neuronal preconditioning; leading to speculation that insulin has a normal, protective effect against stress-related damage in the cerebral vasculature. Our preliminary data also indicate that insulin-dependent effects on the cerebral vasculature are greatly reduced by insulin resistance (IR), a major component of the metabolic syndrome, or by aging. However, mechanisms and possible therapeutic approaches for the restoration of normal cerebral vascular responsiveness to insulin are unknown. We will address two specific aims. Specific Aim 1. Determination of the effects of insulin on cerebral arteries. First, we will characterize the effects of physiological and therapeutic doses of insulin on cerebral arteries of normal Sprague Dawley (SD) rats. Second, we will examine the roles of endothelium and smooth muscle on the integrative changes in vascular tone. Third, we will examine the signaling cascades following activation of insulin receptors. Fourth, we will examine the nature of vasoactive substances mediating insulin effects on the cerebral arteries. Fifth, we will examine whether insulin protects cerebral vascular cells against lethal stress. Specific Aim 2. Determination of the effects of insulin on cerebral arteries during aging and insulin resistance. First, we will characterize responses in cerebral arteries in aged (12-24 month) SD rats. Second, we will characterize responses in cerebral arteries from SD rats suffering from insulin resistance due to consumption of a diet high in fructose. Third, we will elucidate the mechanisms of altered responses in aged and insulin resistant animals. Fourth, we will examine therapeutic approaches for the restoration of normal cerebral arterial responses to insulin in the presence of IR or aging. PUBLIC HEALTH RELEVANCE: Chronic cerebral vascular insufficiency as occurs in IR and in aging and leads to neurological diseases such as non-specific cognitive deficiency, Alzheimer's Disease and strokes but the potential role of insulin has not been studied. Current treatment regimens are not optimal and we expect that the results of our studies will lead to new and improved therapies to prevent or slow the onset of neurological diseases in an obese and aging population.